The pathogenetic mechanisms of the acute myocardial infarction are not yet fully understood. In recent years the role of the coronaryc spasm in the pathogenesis of some forms of angina has been reevaluated and the hypothesis has been suggested that the acute myocardial infarction might in some cases be caused by an extended coronary spasm possibly followed, downstream of the functional stenosis, by alterations of the blood flow and of the vascular wall, with stasis and subsequent platelet aggregation, release of tromboxane (T.times.A.sub.2) and then thrombosis.
The T.times.A.sub.2 may potentiate the vasospastic phenomenon which can be extended to other areas, thus involving potential vessels forming part of the side circulation.
To date, for the treatment of the myocardial ischemia and infarction, some therapeutical proposals have been brought forward and/or practiced, based on the use of:
coronary vasodilators, nitrates PA0 beta-blocking compounds PA0 calcium-antagonizing substances PA0 prostacycline
The nitroderivatives are vasodilating compounds which act directly on all the vessels; the vasodilation as induced by these drugs on the side circulation might cause the intramyocardial blood flow to be redistributed in the presence of a coronary occlusion. In some experimental work nitroglycerin has been able to reduce the myocardial ischemia or infarction, but other workers did not found significant effects with nitroglycerin.
Rather recent clinical studies indicated that nitroglycerin, upon being intravenously injected, may increase the incidence of arrhytmias without modifying the infarction.
Propranolol and the novel cardioselective beta-blocking compounds (Atenolol, Practolol, Metoprolol) have been used with the purpose of reducing the damage caused by the myocardial infarction.
Some authors demonstrated in a dog afflicted with occlusion of the circumflex coronary arteria that Propranolol caused the necrosis to be significantly reduced.
More recent studies, however, did not show significant effects for Propranolol.
Practolol demonstrated effects more interesting than Propranolol in the treatment of the myocardial ischemia, in a comparison study carried out in dogs by evaluating haemodynamic parameters, the oxygen consumption of the myocardium, lactate.
The action of these drugs may be probably attributed to a reduction of the oxygen consumption of the myocardium, as a consequence of the blocking of the sympathic stimulation on the cardiac frequence and contractility.
The calcium antagonizing drugs (Verapamil, Nifedipine, and others), cause the calcium channels to be blocked, and the tone of the vascular smooth muscles to be reduced whereby a coronary but also systemic vasodilation is induced, moreover the blocking of the calcium flow causes the myocardial contractility and oxygen consumption to be reduced. Some authors found in dogs with occlusion of the circumflex coronary arteria a modest but significant reduction of the necrosis after pretreatment with Verapamil; at higher dosages the drug had hypotensive effects and induced a cardiac blocking of various grades. The results obtained with Nifedipine are rather controversial. Nifedipine at high dosages causes a reduction in dogs of aortic pressure, an increase of the cardiac frequency and an increase of the ischemic area; at low dosages it induces a lower pressure diminution and a slight reduction of the ischemic area.
The anti-ischemia effects of Fendiline (negative chronotropic action, increase of the coronary flow) and of Felodipine (preventing action on the ventricle fibrillation induced by the occlusion of the descending coronary in the pig) have been recently described.
The anti-arrhytmic action of Lidocaine, prevailingly attributed to direct electrophysiological effects, is especially interesting in the treatment of ventricular arrhytmias associated with a sympathetic hyperactivity.
Lidocaine, when intravenously injected, reduces the cardial sympathetic activity, this effect would be caused by a central action of the drug.
The Dipyridamole has a dilating action particularly on the coronary small arteriae; this drug is moreover able to interfere with the platelet functionality by potentiating the prostacycline effect or by inhibiting the phosphodiesterases, whereby the intracellular cAMP is increased.
Dipyridamole has induced, under some experimental conditions, an increase of the coronary haematic flow and a reduction of the ischemic area in dogs with occluded coronary artery.
These effects of Dipiridamole are however not evident when the drug gives place to relevant pressure reduction.
Sulfinpyrazone does inhibit the platelet aggregation and the biosynthesis of prostaglandins; this drug has reduced the ventricular arrhytmias and the incidence of the fibrillation in cats with occluded descending coronary. The extension of the ischemic area induced by the occlusion of the coronary however was not reduced by treatment with Sulfinpyrazone.
It has been recently proposed to use prostacyclin (PGI.sub.2) for the treatment of the myocardial acute infarction. PGI.sub.2 was found to be active in the reducing the arrhytmias occurring in the early post-infarction phases in dogs and in rats after ligation of the coronary artery: Harvie C. J. et al; "The action of prostaglandin E.sub.2 and F.sub.1a on myocardial ischaemia-infarction arrhytmias in the dog".
Prostaglandis 16, 885-899, 1978; Cocker S. J. et al, "Thromoboxane and prostacyclin release from ischaemic myocardium in relation to arrhytmias". Nature, 291, 323-324, 1981 and
Au T. L. S. et al "The actions of prostaglandins I.sub.2 and E.sub.2 on arrhythmias procured by coronary occlusion in the rat and dog". Prostaglandins, 18 707-720, 1979).
In a study of the protective effect of PGI.sub.2 on the acute mycoardial ischemia induced in the cat, the hypothesis was made that PGI.sub.2, administered by perfusion, does protect the ischemic myocardium by reducing the oxygen demand of the tissue, through a reduction of the cardiac work and, probably, by inhibiting the platelet aggregation and by preserving the integrity of the myocardial cells (Ogletree M. L. et al, "Studies on the protective effect of prostacyclin in acute myocardial ischemia". Eur. J. Pharmacol., 56 95-103, 1979).
From the above therapeutical picture, which has been necessarily reported in a very condensed manner, it is clear that the problem of the treatment of the myocardial infarction and ischemia has not found to date a therapeutically satisfactory solution.